The goal of this application is to identify and characterize autism susceptibility loci and genes. While numerous linked chromosomal regions of interest have been identified in autism, the traditional approaches to finding disease genes within those regions have encountered unforeseen difficulties. First, these linked regions tend to be large and difficult to narrow, thus the number of candidate genes can be overwhelming. Second, the genes we are looking for are likely to be genes of small effect with types of variability that may be difficult to detect using traditional gene screening methods. Countering these difficulties, however, are a number of significant recent technological advances. Foremost is the ready availability of draft and finished genomic sequence providing the raw material for gene discovery that in the past took months and years to generate. Genome analysis tools and annotation databases are rapidly accelerating our ability to delineate genomic structure and accurately describe a gene's pattern of expression, function, and potential relevance to the disease of interest. Lastly, we are increasingly able to identify functional domains within genes that may be more likely to harbor disease-causing mutations. Our application, therefore, attempts to skirt the obstacles while focusing on the advances. First, we streamline the gene examination process with sophisticated computational bioinformatics technology that automatically identifies, delineates, and extracts expression information for genes in linked regions of interest. Prioritized genes are then screened in multiple autism DNA samples using our high-throughput sequencing and genotyping capabilities, with a preferential focus on protein functional domains. We will also identify and refine linked regions of interest by extending our innovative research on the Broader Autism Phenotype. Laboratory resources that will support this project include 1) a prominent, highperformance computer laboratory dedicated to genomic research; 2) a molecular laboratory with dedicated genotyping and sequencing facilities that has extensive expertise and a track record of success in disease gene discovery; 3) a premier statistical genetics research center; and 4) a wealth of well characterized clinical resources.